This proposal tyrosine kinases and prostate cancer began in 1998 with the development of tyrosine kinase display approach and the first comprehensive tyrosine kinase profile of prostate cancer cells. In the ensuing years, tyrosine kinases involved in androgen independence were identified and the processes characterized. This led to the discovery of Src tyrosine kinase (TK) complex as a central integrator of signals emanating from tyrosine kinase receptor, cytokine receptor and G-protein coupled receptor. Recent studies from several labs including the PI's showed that Src activation is frequently found in castration resistant prostate cancer and Src signatures are found in most metastatic tumors including those which lack androgen receptor expression. The Src TK complex presents novel targets for potential therapeutic intervention. A number of Src inhibitors have entered clinical trials including one based on our study. However, as a monotherapy, Src-targeting therapy has met with limited success, and there is a need for improvement. In the past grant period, with an emphasis on translational research, we have focused on Src selective inhibitors as a potential therapy for prostate cancer and as a probe for critical src-mediated signal pathways involved in prostate cancer progression. We have made significant progress with the major discovery of autophagy as an underlying mechanism of prostate cancer cell's resistance to apoptosis induced by Src-targeting therapy. We also identified several signal pathways associated with Src-mediated prostate carcinogenesis. Built upon the progress made in the past three years, the present proposal continues to focus on the discovery of novel Src oncogenic pathway and the improvement of Src inhibitor-based therapy. Specifically, we will study a new signal pathway which connects Src to ERG via microRNA modulation and the improvement of Src targeting therapy by a combination of autophagy modulators. PUBLIC HEALTH RELEVANCE: The most troubling aspect of prostate cancer is the development of highly metastatic, castration-resistant tumors, which at present are incurable. Src tyrosine kinase is an integrator of oncogenic signals and its activation is a hall mark of metastatic, castration-resistant prostate cancers. We showed that Src is involved in androgen receptor activation in the absence of androgen, contributing to the development of castration-resistant prostate cancer. Others showed that androgen receptor negative metastatic tumors exhibit Src signatures indicating Src activation is involved in sustaining these tumors. Thus, Src signals may be involved in both early and late stage of prostate carcinogenesis. The application or Src-targeting therapy thus deserves attention. However, thus far, clinical trials using Src (or for that matter other tryrosine kinase) inhibitor as monotherpay has met with limited success. The present proposal is specifically designed to improve Src-targeting therapy based on the laboratory discoveries and progress made in the past grant period.